Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial | Genetics and Genomics | JAMA Oncology | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 35.153.100.128. Please contact the publisher to request reinstatement.
1.
Pavlidis  N, Pentheroudakis  G.  Cancer of unknown primary site.   Lancet. 2012;379(9824):1428-1435. doi:10.1016/S0140-6736(11)61178-1 PubMedGoogle ScholarCrossref
2.
Varadhachary  GR, Raber  MN.  Cancer of unknown primary site.   N Engl J Med. 2014;371(8):757-765. doi:10.1056/NEJMra1303917 PubMedGoogle ScholarCrossref
3.
Massard  C, Loriot  Y, Fizazi  K.  Carcinomas of an unknown primary origin—diagnosis and treatment.   Nat Rev Clin Oncol. 2011;8(12):701-710. doi:10.1038/nrclinonc.2011.158 PubMedGoogle ScholarCrossref
4.
Rassy  E, Pavlidis  N.  Progress in refining the clinical management of cancer of unknown primary in the molecular era.   Nat Rev Clin Oncol. 2020. doi:10.1038/s41571-020-0359-1 PubMedGoogle Scholar
5.
Greco  FA, Erland  JB, Morrissey  LH,  et al.  Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin.   Ann Oncol. 2000;11(2):211-215. doi:10.1023/A:1008369812295 PubMedGoogle ScholarCrossref
6.
Briasoulis  E, Kalofonos  H, Bafaloukos  D,  et al.  Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.   J Clin Oncol. 2000;18(17):3101-3107. doi:10.1200/JCO.2000.18.17.3101 PubMedGoogle ScholarCrossref
7.
Greco  FA, Pavlidis  N.  Treatment for patients with unknown primary carcinoma and unfavorable prognostic factors.   Semin Oncol. 2009;36(1):65-74. doi:10.1053/j.seminoncol.2008.10.005 PubMedGoogle ScholarCrossref
8.
Pavlidis  N, Khaled  H, Gaafar  R.  A mini review on cancer of unknown primary site: a clinical puzzle for the oncologists.   J Adv Res. 2015;6(3):375-382. doi:10.1016/j.jare.2014.11.007 PubMedGoogle ScholarCrossref
9.
Petrakis  D, Pentheroudakis  G, Voulgaris  E, Pavlidis  N.  Prognostication in cancer of unknown primary (CUP): development of a prognostic algorithm in 311 cases and review of the literature.   Cancer Treat Rev. 2013;39(7):701-708. doi:10.1016/j.ctrv.2013.03.001 PubMedGoogle ScholarCrossref
10.
Economopoulou  P, Mountzios  G, Pavlidis  N, Pentheroudakis  G.  Cancer of unknown primary origin in the genomic era: elucidating the dark box of cancer.   Cancer Treat Rev. 2015;41(7):598-604. doi:10.1016/j.ctrv.2015.05.010 PubMedGoogle ScholarCrossref
11.
Moran  S, Martínez-Cardús  A, Sayols  S,  et al.  Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis.   Lancet Oncol. 2016;17(10):1386-1395. doi:10.1016/S1470-2045(16)30297-2 PubMedGoogle ScholarCrossref
12.
Pentheroudakis  G, Greco  FA, Pavlidis  N.  Molecular assignment of tissue of origin in cancer of unknown primary may not predict response to therapy or outcome: a systematic literature review.   Cancer Treat Rev. 2009;35(3):221-227. doi:10.1016/j.ctrv.2008.10.003 PubMedGoogle ScholarCrossref
13.
Pentheroudakis  G, Pavlidis  N, Fountzilas  G,  et al.  Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary.   Mol Cancer. 2013;12:57. doi:10.1186/1476-4598-12-57 PubMedGoogle ScholarCrossref
14.
Varadhachary  G.  New strategies for carcinoma of unknown primary: the role of tissue-of-origin molecular profiling.   Clin Cancer Res. 2013;19(15):4027-4033. doi:10.1158/1078-0432.CCR-12-3030 PubMedGoogle ScholarCrossref
15.
Varadhachary  GR, Spector  Y, Abbruzzese  JL,  et al.  Prospective gene signature study using microRNA to identify the tissue of origin in patients with carcinoma of unknown primary.   Clin Cancer Res. 2011;17(12):4063-4070. doi:10.1158/1078-0432.CCR-10-2599 PubMedGoogle ScholarCrossref
16.
Hainsworth  JD, Rubin  MS, Spigel  DR,  et al.  Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute.   J Clin Oncol. 2013;31(2):217-223. doi:10.1200/JCO.2012.43.3755 PubMedGoogle ScholarCrossref
17.
Hayashi  H, Kurata  T, Takiguchi  Y,  et al.  Randomized phase II trial comparing site-specific treatment based on gene expression profiling with carboplatin and paclitaxel for patients with cancer of unknown primary site.   J Clin Oncol. 2019;37(7):570-579. doi:10.1200/JCO.18.00771 PubMedGoogle ScholarCrossref
18.
Takeda  M, Sakai  K, Terashima  M,  et al.  Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer.   Ann Oncol. 2015;26(12):2477-2482. doi:10.1093/annonc/mdv475 PubMedGoogle ScholarCrossref
19.
Rehm  HL, Bale  SJ, Bayrak-Toydemir  P,  et al; Working Group of the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee.  ACMG clinical laboratory standards for next-generation sequencing.   Genet Med. 2013;15(9):733-747. doi:10.1038/gim.2013.92PubMedGoogle ScholarCrossref
20.
Fizazi  K, Greco  FA, Pavlidis  N, Daugaard  G, Oien  K, Pentheroudakis  G; ESMO Guidelines Committee.  Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.   Ann Oncol. 2015;26(suppl 5):v133-v138. doi:10.1093/annonc/mdv305 PubMedGoogle ScholarCrossref
21.
Greco  FA, Burris  HA  III, Litchy  S,  et al.  Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: a Minnie Pearl Cancer Research Network study.   J Clin Oncol. 2002;20(6):1651-1656. doi:10.1200/JCO.2002.20.6.1651 PubMedGoogle ScholarCrossref
22.
Greco  FA, Rodriguez  GI, Shaffer  DW,  et al.  Carcinoma of unknown primary site: sequential treatment with paclitaxel/carboplatin/etoposide and gemcitabine/irinotecan: a Minnie Pearl Cancer Research Network phase II trial.   Oncologist. 2004;9(6):644-652. doi:10.1634/theoncologist.9-6-644 PubMedGoogle ScholarCrossref
23.
Hainsworth  JD, Spigel  DR, Clark  BL,  et al.  Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial.   Cancer J. 2010;16(1):70-75. doi:10.1097/PPO.0b013e3181c6aa89 PubMedGoogle ScholarCrossref
24.
Hainsworth  JD, Daugaard  G, Lesimple  T,  et al.  Paclitaxel/carboplatin with or without belinostat as empiric first-line treatment for patients with carcinoma of unknown primary site: a randomized, phase 2 trial.   Cancer. 2015;121(10):1654-1661. doi:10.1002/cncr.29229 PubMedGoogle ScholarCrossref
25.
Ross  JS, Wang  K, Gay  L,  et al.  Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies.   JAMA Oncol. 2015;1(1):40-49. doi:10.1001/jamaoncol.2014.216 PubMedGoogle ScholarCrossref
26.
Greco  FA, Lennington  WJ, Spigel  DR, Hainsworth  JD.  Molecular profiling diagnosis in unknown primary cancer: accuracy and ability to complement standard pathology.   J Natl Cancer Inst. 2013;105(11):782-790. doi:10.1093/jnci/djt099 PubMedGoogle ScholarCrossref
27.
Erlander  MG, Ma  XJ, Kesty  NC, Bao  L, Salunga  R, Schnabel  CA.  Performance and clinical evaluation of the 92-gene real-time PCR assay for tumor classification.   J Mol Diagn. 2011;13(5):493-503. doi:10.1016/j.jmoldx.2011.04.004 PubMedGoogle ScholarCrossref
28.
Meiri  E, Mueller  WC, Rosenwald  S,  et al.  A second-generation microRNA-based assay for diagnosing tumor tissue origin.   Oncologist. 2012;17(6):801-812. doi:10.1634/theoncologist.2011-0466 PubMedGoogle ScholarCrossref
29.
Varghese  AM, Arora  A, Capanu  M,  et al.  Clinical and molecular characterization of patients with cancer of unknown primary in the modern era.   Ann Oncol. 2017;28(12):3015-3021. doi:10.1093/annonc/mdx545 PubMedGoogle ScholarCrossref
30.
Drilon  A, Siena  S, Ou  SI,  et al.  Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).   Cancer Discov. 2017;7(4):400-409. doi:10.1158/2159-8290.CD-16-1237 PubMedGoogle ScholarCrossref
31.
Román  M, Baraibar  I, López  I,  et al.  KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target.   Mol Cancer. 2018;17(1):33. doi:10.1186/s12943-018-0789-x PubMedGoogle ScholarCrossref
32.
Nagasaka  M, Li  Y, Sukari  A, Ou  SI, Al-Hallak  MN, Azmi  AS.  KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?   Cancer Treat Rev. 2020;84:101974. doi:10.1016/j.ctrv.2020.101974 PubMedGoogle Scholar
33.
Sinicrope  FA, Okamoto  K, Kasi  PM, Kawakami  H.  Molecular biomarkers in the personalized treatment of colorectal cancer.   Clin Gastroenterol Hepatol. 2016;14(5):651-658. doi:10.1016/j.cgh.2016.02.008PubMedGoogle ScholarCrossref
34.
Hyman  DM, Puzanov  I, Subbiah  V,  et al.  Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations.   N Engl J Med. 2015;373(8):726-736. doi:10.1056/NEJMoa1502309 PubMedGoogle ScholarCrossref
35.
Haratani  K, Hayashi  H, Takahama  T,  et al.  Clinical and immune profiling for cancer of unknown primary site.   J Immunother Cancer. 2019;7(1):251. doi:10.1186/s40425-019-0720-z PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    October 15, 2020

    Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial

    Author Affiliations
    • 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
    • 2Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
    • 3Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
    • 4Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan
    • 5Department of Medical Oncology, International Medical Center, Saitama Medical University, Hidaka, Japan
    • 6Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
    • 7Department of Medical Oncology, Hiroshima City Hospital Organization, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
    • 8Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
    • 9Medical Oncology Division, Hyogo Cancer Center, Akashi, Japan
    • 10Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
    • 11Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
    • 12Department of Respiratory Medicine and Medical Oncology, Gifu Municipal Hospital, Gifu, Japan
    • 13Division of Clinical Oncology, Shizuoka Cancer Center, Shizuoka, Japan
    • 14Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Japan
    • 15Chiba Cancer Center, Research Institute, Chiba, Japan
    • 16Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
    • 17Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
    JAMA Oncol. 2020;6(12):1931-1938. doi:10.1001/jamaoncol.2020.4643
    Key Points

    Question  Does site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by next-generation sequencing, have clinical use for patients with cancer of unknown primary site?

    Findings  This phase 2 nonrandomized clinical trial of such site-specific treatment in 97 patients with cancer of unknown primary site revealed a 1-year survival probability of 53.1%, with a durable response to targeted therapy being observed in patients with actionable genetic alterations.

    Meaning  Site-specific treatment, including guided targeted therapy based on next-generation sequencing, is a promising strategy for patients with cancer of unknown primary site and warrants further investigation in a randomized clinical trial.

    Abstract

    Importance  Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.

    Objective  To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.

    Design, Setting, and Participants  This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.

    Interventions  RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.

    Main Outcomes And Measures  The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.

    Results  Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non–small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.

    Conclusions and Relevance  This study’s findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.

    Trial Registration  UMIN Identifier: UMIN000016794

    ×